Substituted trifluoromethylthio- and trifluoromethoxyphenyl sulfonylureas



United States Patent 3 021 368 SUBSTITUTED TRrFiUoizoME'rnYLTrno- AND TRIFLUGROMETHOXYPHENYL SULFONYL- UREAS Benjamin Blank, Philadelphia, and James F. Kerwin,

Broomall, Pa., assignors to Smith Kline & French Laboratories, Philadelphia, Pa., a corporation of Pennsylvama No Drawing. Fil'ed Apr. 22, 1959, Ser. No. 807,998 9 Claims. (Cl. 260-553) This invention relates to novel substituted trifluoromethylthioand trifluoromethoxyphenyl sulfonylureas having valuable pharmacological activity. Further this FORMULA I @sm-nn-o O-NE-BI when R represents trifluoromethylthio or trifiuoromethoxy; and

R represents lower alkyl, lower cycloalkyl, lower alkoxy-alkylene or lower alkyl mercapto-alkylene.

The R moiety is preferably in the para position of the benzene ring.

'Advantageous compounds ofthis invention are represented by the following fundamental formula:

FORMULA ll when:

R represents trifluoromethylthio or trifluoromethoxy; and

R represents lower alkyhpreferably contain ng from 2 to 5 carbon atoms;'lower cycloalkyl, preferably con- =taining from 5 to 6 carbon atoms; lower alkoxy-alkylene, the lower allro'xy moiety preferably containing from 1 to 3 carbon atoms and the alkylene' moiety preferably containing-from 2 to *4 carbon atoms; or lowebalkyhmer- -'capto-alkylene, the lower 'alkyl mercapto moiety preferably containing from 1' to3 c'arbonatomsand the alkylene moiety preferably containin'g from 2 to '4 carbon atoms.

Preferred compounds of this invention are represented :bvzthe following fundamental formula:

FORMULA 1H 1 R represents *tritluoromethylthio or trifluoromethoxy; and

"R represents propyl, *butyl, cyclohexyl, methoxyethyl,

when:

methoxypropyl,methylmercaptoethyl or methylmercaptopropyl.

Particularly. preferred and advantageous compounds of :thisinvention arerepresented. by Eormula III above when R represents propyl or butyl.

2 When the term"lower alkyl is used herein, aliphatic groups having not more than 6 carbon atomsare indicated except where otherwise specified. When the term 'lower cycloalkylhis used herein, cycloaliphatic groups having not more than 6 carbon atoms .are indicated. When the term lower alkoxy is usedherein, aliphatic groups having not more than 4 carbon atoms are indicated except where otherwise specified. When the term alkylene is used in connection with acarbon chain, aliphatic groups having not more than 6.carbon atoms are indicated except where otherwise specified. When the term lower alkyl mercapto is used herein, aliphatic groups having not more than 4 carbon atoms are indicated except where otherwise specified. The aliphatic groups herein defined may be straight or branched chain.

The novel trifiuorornethylthioand trifiuoromethoxybenzenesulfonamides of this invention useful as intermediates in the preparation of the sulfonylureas described in Formula I above, as is outlined more fully hereinafter,

- D5 0 zNH:

when:

R represents trifiuoromethylthio or trifluorornethoxy.

The R, moiety is preferably in the para position of the benzene ring.

The sulfonamides'of Formula IV are advantageously prepared from the corresponding trifluoromethylthioand trifluoromethoxy substituted benzenederivatives. Thus, a solution of the appropriate substituted benzene derivative in an unreactive organic solvent, for example chloroform or carbon tetrachloride, is reacted with'an excess (at least two equivalents) of chlorosulfonic'acid at a temperature in the range of from .0 to 30 C. for from two to six hours. The reaction mixture is then treated with ice and water to decompose the excms chlorosulfonic acid and the resultant organic phase containing the substituted benzenesulfonyl chloride is evaporated to dryness with ammonium carbonate. The residue is Water-washed to give the corresponding trifiuoromethylthio- 'or trifluoromethoxybenzenesulfonarnides which are then further rcacted as described hereinafter to prepare the sulfonylurea products of this invention.

Alternatively, the above'substituted benzene sulfonyl chlorides are prepared from the corresponding sulfonic acid by reaction with phosphorus pentachlori'de' or phosphorus oxychloride. Also, the sulfonyl chlorides are converted to the sulfonarnides by reaction withaqueous am- 'monia.

An advantageous method-of preparation of thenovei trifluorornethylthioand tr-ifluoromethoxyphenyl sulfonyl- 'urea derivatives of this invention comprises the'reaction of the appropriate substitutedbenzenesulfonamide with an isocyanate, illustrated as follows:

in which R, and R are as defined above. In this method,the isocyanateiis reacted with a'stirred solution of the sulfonamidedissolved inone equivalent of an alkali metal hydroxide such as sodium hydroxide, containing a volume of an unreactive organic solvent such as acetone, sufiicient to maintain a homogeneous solution, at a temperature in therange of lfromOto 60:C.:for,from.one

to Zeight .hours. The product ..is obtained: by removing the organic solventand acidifying the residue withza dilute Patented Feb. 13, 1962 acid such as a mineral acid, for example hydrochloric acid, or a weak organic acid, for example acetic acid. The solid is removed by filtration and purified by recrystallization. This method is especially advantageous when the appropriate isocyanateis readily available.

Following the method outlined above, the sulfonylurea products wherein R of Formula I is lower alkoxyalkylene or lower alkyl mercapto-alkylene are also advantageously prepared by first reacting the sulfonamide with an isocyanate containing a reactive alkyl ester moiety for example a haloalkyl moiety, preferably chloroalkyl, and the thus formed haloalkyl urea derivative is further reacted with an appropriate alcohol or mercaptan so as to yield the said sulfonylurea products. The alkali metal salt, preferably sodium, of the alcohol or mercaptan is used in the above method and the reaction is run in an unreactive organic solvent such as ethanol or isopropanol, at reflux temperature for from two to six hours. The reaction mixture is filtered and acidified to give the product upon cooling.

Alternatively, the sulfonylureas of this invention are prepared by the reaction of trifiuoromethylthioor trifluoromethoxyphenylsulfonyl isocyanate (obtained by standard procedures such as for example by the reaction of trifluoromethylthio-or trifluoromethoxybenzenesulfonamide with phosgene) with a primary amine containing the R moiety as defined in Formula I, outlined as follows:

Dem-N R:NH9 R1 Q-SOr-NH-OO-NH-Ra R: In this method, the isocyanate is reacted with a stirred solution of the amine dissolved in an unreaetive organic solvent such as for example benzene or dioxane, at a temperature in the range of from 0 to 60 C. for from one to eight hours. The product is isolated by cooling and filtering, and is purified by recrystallization.

Further, the sulfonylureas of this invention are prepared by other methods useful in urea syntheses. For example, trifluoromethylthioor trifiuoromethoxyphenylsulfonylurea (prepared by standard methods such as for example by the reaction of trifluoromethylthioor trifiuoromethoxybenzenesulfonamide with potassium cyanate) is reacted with R NH to yield the desired prod: not. Also, trifiuoromethylthioor trifluoromethoxybenzenesulfonamide is reacted with ethyl chlorocarbonate to give the corresponding N-carbethoxy-sulfonamide derivative which is in turn reacted with R -NH to yield the .7 sulfonylurea products.

It will be obvious to one skilled in the art that other methods are adaptable for the preparation of the sulfonylureas of this invention. The foregoing is a general description of several advantageous methods. Of particular advantage as a preparative method is the reaction of trifluoromethylthioor triiiuoromethoxybenzenesulfonamide with R -NCO, R being defined as in Formula I.

The following examples illustrate the compounds of this invention and the procedures for their preparation,

' but are not to be construed as limiting the invention except within the definition of the fundamental Formula 1 given above.

. Example I To a stirred solution of 53.4 g. of trifiuoromethylthiophenol in 150 ml. of chloroform cooled to 5 C. is added 186.0 g. of chlorosulfonic acid, the temperature main- -tained below C. 'After addition is complete, the mixture is stirred with cooling for one hour and then at room temperature for an additional two hours. The ,mixture is added dropwise to a stirred mixture of ice and water. The-layers are separated and the aqueous layer is extracted with chloroform. The combined chloroform solution is dried and evaporated to dryness with 100.0 g. of ammoniumcarbonate. The residue is suspended in water, filtered, and washed with water to give the product, p-triliuoromethylthiobenzenesulfonamide. Recrystallization from 50% aqueous ethanol yields pure crystals melting at l60-l62 C.

Example 2 To a stirred solution of 12.0 g. of trifluoromethoxybenacne in 40 ml. of chloroform cooled to 05 C. isadded 46.0 g. of chlorosulfonic acid at such a rate that the temperature does not exceed 10 C. The solution is stirred one hour with cooling during which time hydrogen chloride is vigorously evolved. The reaction mixture is stirred an additional two hours at room temperature and is then added dropwise to a stirred mixture of ice and water. The layers are separated and the aqueous layer is extracted with chloroform. The chloroform phases are combined, dried over magnesium sulfate, and evaporated to dryness with 25.0 g. of ammonium carbonate. The residue is suspended in water, filtered, and washed with water. The solid is recrystallized from toluene to give p-trifluoromethoxybenzenesulfonamide, M.P. 144-145 C.

Example 5' To a solution of 2.6 g. of p-trifluoromethylthiobenzenesulfonamide in 10 ml. of 1 N sodium hydroxide and 10 ml. of acetone cooled to 0-5 C. is added dropwise a solution of 1.1 g. of n-butyl isocyanate in'S ml. of acetone, the temperature maintained below 10 C. during the addition. The resulting mixture is stirred one hour with cooling and then two hours at room temperature. The acetone is removed at reduced pressure at a bath temperature of about 40 C. and the aqueous residue is acidified with dilute hydrochloric acid with cooling. The solid is filtered, washed with water, and recrystallized from aqueous methanol to give (N -p-trifluoromethylthiophenylsulfonyl-N -n-butyl)-urea, M.P. 119-120 C.

Example 4 A solution of 2.3 g. of n-propyl isocyanate in 10 ml. of acetone is added dropwise to a solution of 6.4 g. of p-trifiuoromethylthiobenzenesulfonamide in 25 ml. of l N sodium hydroxide and 25 ml. of acetone at 05 C. The mixture is stirred one hour with cooling and then two hours at room temperature. The acetone is removed in vacuo and the residue acidified with dilute hydrochloric acid to give the product (N -p-trifluoromethylthiophenylsulfonyl-N -n-propyl)urea,-M.P. 137-1385 C.

Example 5 To a solution of 4.8 g. of p-trifiuoromethoxybenzenesulfonamide in 20 ml. of 1 N sodium hydroxide and 20 ml. of acetone cooled to 0-5 C. is added dropwise a solution of 2.2 g. of n-butyl isocyanate in 10 ml. of acetone, maintaining the temperature below 10 C. during the addition. The mixture is then stirred one hour with cooling and two hours at room temperature. The acetone is removed in vacuo and the residue is acidified with dilute hydrochloric acid. The ,solid is filtered, washed with water, and recrystallized from aqueous methanol to yield (N -p-trifluoromethoxyphenylsulfonyl- N -n-buty1)urea, M.P. 107-109" C.

Example 6 A solution. of 2.8 g. of n-propyl isocyanate in 10 ml. of acetone is added dropwise to a solution of 7.2 g. of p-trifiuoromethoxybenzenesulfonamide in 30 ml. of 1 N sodium hydroxide and 30 ml. of acetone at 0-5 C. The mixture is stirred one hour with cooling and then two hours at room'temperature. The acetone is removed in vacuo and the residue acidified with dilute hydrochloric acid to give (N -p-trifluoromethoxyphenylsulfonyl-N -npropyl)urea, M.P. 123-124 C.

Example 7 A solution of 31.0 g. of p-trifluoromethylthiophenylsulfonyl isocyanate (prepared from the reaction of 35.0 g. of p-trifiuoromethylthiobenzenesulfonamide with an excess of phosgene and heating the carbamyl chloride thus formed) in 125 ml. of benzene is added in portions to a solution of 9.9 g. of cyclohexylamine in 100 ml. of benzene. The solution is stirred for six hoursat 4050 C. To the cooled reaction mixture, 300 ml. of ether is added and the solid which separates is filtered and recrystallized to give (N -p-trifluoromethylthiophcnylsulfonyl-N -cyclohexyl)urea.

Similarly, following the above procedure, 15.5 g. of p-trifluoromethylthiophenylsulfonyl isocyanate and 4.3 g. of cyclopentylamiue are reacted to yield (N -p-trifluoromethylthiophenylsulfonyl-N -cyc1opentyl)urea.

Example 8 A mixture of 3.0 g. of Z-methoxyethylamine and 2.8 g. of p-trifluoromethoxyphenylsulfonylurea (prepared from the reaction of 3.2 g. of p-trifiuoromethoxybenzenesulfonamide with potassium isocyanate) in 20 ml. of glacial acetic acid is heated at 95 C. with stirring for one hour. The reaction mixture is cooled and then diluted with 100 ml. of water. The solid which precipitates is removed by filtration, washed with water and recrystallized to give [N -(p-trifluoromethoxyphenylsulfony1)-N (Z-methoxyethyl) -urea.

Example 9 A solution of 8.8 g. of p-ttifluoromethoxyphenylsulfonyl isocyanate (prepared from the reaction of 11.0 g. of p-trifluoromethoxybenzenesulfonamide with an excess of phosgene and heating the carbamyl chloride thus formed) in 50 ml. of benzene is added in portions to a solution of 3.0 g. of cyclohexylamine in 50 ml. of benzene. The solution is stirred for six hours at 4050 C. and worked up as described in Example 7 to yield (N -ptrifluoromethoxyphenylsultonyl-N-cyclohexyl)urea.

Example 10 To. .a so1'ution.of.25.7 g. of .p-trifluoromethylthiobenzenesulfonamide in 125 ml. of 1 N, sodium hydroxide and'200 m1. of acetone is added dropwise with stirring and cooling a solution of 12.1 g. of 2-chloroethylisocyanatein 100. ml. 10f acetone. The reaction mixture is then stirred for an additional two hours. The acetone is removed and the residue is acidified with aqueous acetic acid. The solid is filtered and recrystallized to give [N (p-trifluoromethylthiophenylsulfonyl) N -(2-chloroethyl) lurea.

A mixture of 37.2 g. of the 2-chloroethyl urea prepared above, 4.6 g. of sodium and 16.0 g. of methylmercaptan in 300 ml. of ethanol is refluxed for three hours.

The reaction mixture is cooled, diluted with water and filtered. The filtrate is acidified with acetic acid and cooled to precipitate the product, [N -(p-trifiuoromethylthiopheuylsulfony1)-N -(Z-methylmercaptoethyl) ]urea.

Example 11 Example 12 Example 13 A solution of 3.0 g. of p-trifluoromethoxypbeuylsulfonyl isocyanate in 30 ml. of benzene is added dropwise to a solution of 1.0 g. of n-hexylamine in 20ml. of benzene. The resulting solution is stirred for eight hours at 60 C., cooled and diluted with ether to yield (N -ptrifiuoromethoxyphenylsulfonyl-N -n-hexyl)urea.

Example 14 A solution of 2.5 g. of B-methoxypropyl isocyanate in 10 ml. of acetone is added dropwise with stirring to a solution of 5.1 g. of p-trifiuoromethylthiobenzenesulfonamide in 20 ml. of l N sodium hydroxide and 20 ml. of acetone at 5-10" C. The mixture is stirred for four hours at 40-50 C., cooled and the acetone removed. The residue is acidified with dilute hydrochloric acid to yield [N -(p-trifiuoromethylthiopheuylsulfonyl)-N (3-methoxypropyl) ]-urea Similarly, following the above procedure, 3.1 g. of 'Z-butoxyethyl isocyanate and 5.1 g. of p-trifluoromethylthiobenzenesulfonamide are reacted to give [N -(p-trifluoromethylthiophenylsulfonyl) N (2 butoxyethyl)]urea.

Example 15 A mixture of 3.7 g. of [N -(p-trifluoromethylthiophenylsulfonyl)-N3-(2-chloroethyl)]urea (prepared as in Example 10) and 1.6 g. of sodium isopropoxide in ml. of isopropanol is heated at reflux for four hours. The reaction mixtureis cooled, diluted with water and filtered. Acidification of the filtratewith acetic acid and cooling yields the product, [Nl-(p-trifiuoromethylthiophenylsulfonyl)-N -(2-isopropoxyethyl)Jurea. I

Example 16 A solution of 29.4 g. of p-trifluoromethoxyphenylsulfonyl isocyanate in 250 ml. of benzene is added dropwise with stirring to a solution of 10.3 g. of 3-methoxyisobutylamine in ml. of benzene. The resulting solution is stirred for an additional six hours at 50-60" C., cooled and diluted with ether. The solid which separates is removed and purified by recrystallization to give [N (p trifluoromethoxyphenylsulfonyl) N (3- methoxyisobuty1)]urea.

Example 18 A solution of 7.3 g. of p-trifiuoromethoxyphenylsulfonyl isocyanate in 100 m1. of benzene is added dropwise with stirring to a solution of 1.5 g. of isopropylamine in 50 A. solution of 15.5 g. of p-trifluoromethylthiophenylsulfonyl isocyanate in 200ml. of benzene is added dropwise'to a stirred solutionIof 6.7g. of .Z-butylmercaptoethylamine in 100 ml. of benzene. The solution is stirred for six hours at 50-60 C., cooled and diluted with ether.

The resultant solid is purified by recrystallization to give mulaz in which R; is a-member selected from the group-consisting of trifluoromethylthio and trifluoromethoxyyand R isga' member selected from'the group consisting of lower alkyl of from'2 to carbon atoms; lower cycloalkyl of from 5 to 6 carbon atoms; lower alkoxyalkylene,

the lower alkoxy moiety is from 1 to 3 carbon atoms and the alkylene moiety'is of from 2 to 4 carbon atoms; and lower alkyl mercapto-alkylene, the lower alkyl mercapto moiety is offfrom 1- to 3 carbon atoms and the alkylene moiety is of from 2 to 4 carbon atoms.

2. A chemical compound having the followingformula:

R1 in which R1 is a member selectedfi-om' the group consisting of trifluoromethylthio and trifluoromethoxy. 3. A chemical compound having the following formula:

c ESQ-S Of-NH-G O-NH-CHnCHzCHzCH;

8'. 4. A chemical compound having the following formula: r i

' o ESQSOrNH-C o-ecn-omorncm 5. A chemical compound having the following formula:

omo-Q-swmn-oo-mkoenomom 6. A chemical compound having the following formula:

o moQSOPNH-G o-Nrr-omornomscrr,

STA chemicalcompoun'd having the following formula: V V

0 ms QB oaNHi 9. A chemical compound having the following for mule:

C F:OV 3'SO:NH;v References Cited in the file of this patent UNITED STATES PATENTS 2,891,960 Ruschiget a1. June 23, 1959 V FOREIGN PATENTS 802,885- Great Britain Oct. 15, 1958 196,413 Austria Mar. 25, 1953 1,003,716 Germany Mar. 7,1957 1,024,074 Germany Feb. 13, 1958 559,530 Belgium Nov. 16, 1957 Ruschig et '21.: Ann -Porsch vol. 8, No. 7 PP- 448- v 454 (July 1958); 

1. A CHEMICAL COMPOUND HAVING THE FOLLOWING FORMULA: 